Common genetic variants sometimes exert a strong influence on expression levels and/or functions of the gene products. Such common variants can be associated with susceptibility to diseases and/or pharmacological responsiveness (Dean M, et al., (1996) Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Hemophilia Growth and Development Study, Multicenter AIDS Cohort Study, Multicenter Hemophilia Cohort Study, San Francisco City Cohort, ALIVE Study. Science 273:1856-1862; Risch N, et al., (1996) The future of genetic studies of complex human diseases. Science 273:1516-1517; and Kruglyak L (1997) The use of a genetic map of biallelic markers in linkage studies. Nat Genet 17: 21-24).
SNPs are most simple and conventional DNA polymorphisms. SNPs are present in every several hundred nucleotides on average throughout the genome and relatively easy to genotype and analyze the data. Recently, it has been hypothesized that common variants may contribute to common diseases and pharmacological traits, so-called “common disease-common variant” hypothesis (Risch N, et al., (1996) The future of genetic studies of complex human diseases. Science 273: 1516-1517). In that point of view, SNPs are useful markers for identifying genes responsible for common diseases (Kruglyak L (1999) Prospects for whole-genome linkage disequilibrium mapping of common disease genes. Nat Genet 22: 139-144).
Myocardial infarction is one of the most common diseases in Japan. Obesity, smoking, diabetes, high blood pressure, and hyperlipidemia are well known risk factors of myocardial infarction. However, family history is an independent risk factor of myocardial infarction in various populations (Andresdottir M B, et al., (2002) Fifteen percent of myocardial infarctions and coronary revascularizations explained by family history unrelated to conventional risk factors, The Reykjavik Cohort Study. Eur Heart J 23: 1637-1638; Piegas LS, et al., AFIRMAR Study Investigators, (2003) Risk factors for myocardial infarction in Brazil, Am Heart J 146: 331-338; and Yarnell J, et al., (2003) Family history, longevity, and risk of coronary heart disease: the PRIME Study, Int J Epidemiol 32: 71-77). Many candidate gene approaches have been used for identifying the susceptiblility gene for myocardial infarction (Topol E J, et al., (2001) Single nucleotide polymorphisms in multiple novel thrombospondin genes may be associated with familial premature myocardial infarction, Circulation 104: 2641-2644; Fumeron F, et al., (2002) Serotonin transporter gene polymorphism and myocardial infarction: Etude Cas-Temoins de l'Infarctus du Myocarde (ECTIM), Circulation 105: 2943-2945; and Yamada Y, et al., (2002) Prediction of the risk of myocardial infarction from polymorphisms in candidate genes, N Engl J Med 347: 1916-1923). However, there exist almost no reports concerning systemic surveys for identification of genes associated with myocardial infarction.
The present inventors have constructed a large SNP database including SNPs based on over 170,000 or more genes (Haga H, et al., (2002) Gene-based SNP discovery as part of the Japanese Millennium Genome Project: identification of 190,562 genetic variations in the human genome, Single-nucleotide polymorphism, J Hum Genet 47: 605-610). The present inventors have also developed a high-throughput genotyping system by which 450,000 genes were genotyped per day (Ohnishi Y, et al., (2001) A high-throughput SNP typing system for genome-wide association studies, J Hum Genet 46: 471-477).